Inhibition of epidermal growth factor receptor (EGFR) signaling is an important approach to the targeted treatment of cancer. However, although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is primarily effective only in a limited number of lung cancers that express specific EGFR mutations and are oncogene addicted. Thus, the ability to render cancer cells with primary EGFR resistance sensitive to EGFR inhibition is potentially of enormous clinical value, given the wide prevalence of EGFR overexpressing cancers with primary resistance to EGFR inhibition. Aberrant epidermal growth factor receptor (EGFR) signaling is common in glioblastoma (GBM). GBM is a devastating disease and, even with the best treatment, the prognosis is dismal. No targeted treatment is effective in GBM. EGFR gene amplification and mutation are common in GBM and multiple trials of EGFR inhibition in GBM have been conducted. However, EGFR inhibition has not been successful in GBM. The failure of targeted treatments in GBM has led to an intensive effort to understand mechanisms that mediate resistance to targeted treatment. Here, we propose a mechanism that mediates primary resistance to EGFR inhibition in GBM and a strategy to overcome it. We propose that the primary resistance of EGFR expressing GBMs results from a rapid adaptive response that prevents cell death from a sudden loss of EGFR signaling. This adaptive response can be detected in glioma cells expressing either EGFRwt or the oncogenic EGFRvIII mutant. Our preliminary data indicate that in glioma cells expressing either EGFRwt or EGFRvIII, Erlotinib triggers a rapid homeostatic response that involves activation of the transcription factor Nrf2 signaling network. Nrf2 regulates key downstream signaling networks that are critical mediators of therapeutic resistance to EGFR inhibition in GBM. Our preliminary data indicate that a combined inhibition of EGFR and Nrf2 overcomes the primary resistance of GBMs to EGFR inhibition in cell culture as well as in an orthotopic model of GBM. In Specific Aim 1: we examine the effector mechanisms downstream of Nrf2 that mediate mediating primary resistance to EGFR inhibition in glioma cells In Specific Aim 2 we examine the mechanisms that regulate activation of Nrf2 in response to EGFR inhibition in GBM. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and Nrf2 or inhibition of key signaling networks downstream of Nrf2 in a preclinical mouse orthotopic model examining the hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform GBMs with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and Nrf2 inhibitors are in clinical use, this approach could be rapidly tested in patients. The proposal addresses critical unmet needs in the management of GBM, and could have a transformative impact on the way GBM is treated.